Known as Mendelian randomization, this technique uses genetic variants, called alleles, to test whether specific risk factors are associated with or cause certain disease outcomes. This strategy could help researchers better understand existing, unmeasured confounding factors that can correlate to both dependent and independent variables, particularly environmental exposures, impacting observational studies.

The basic Mendelian randomization principle is if an environmental exposure, such a urate levels, is linked to an outcome, such as cardiovascular disease, a genetic variation will be present. Identifying these genetic variants could be helpful with rheumatological diseases.

To better understand Mendelian randomization and how it touches rheumatological conditions, researchers, led by Philp C. Robinson from the University of Queensland School of Medicine in Australia, published a systematic literature review in Nature, analyzing existing results and how they can be applied to rheumatology.

“Mendelian randomization can shed new light on cause-effect relationships in rheumatology, helping to make the case for investment in confirmatory intervention trials and to generate new hypotheses regarding pathological mechanisms and aetiology,” investigators wrote. “The technique also enables experiments to be performed that would otherwise be unethical, logistically difficult or prohibitively expensive.”

Not only can Mendelian randomization studies potentially direct clinical practice, but it can also help prioritize causal pathway interventions and help avoid unnecessary clinical trials. It can be incorporated into randomized clinical trials that test therapies for common disease risk factors, potentially explaining why targeted-intervention benefits often are lower than expected, researchers said.

Any selected genetic variants shouldn’t be associated with confounders, and they shouldn’t have pleiotropic effects. For Mendelian randomization results to be valid, investigators must satisfy three criteria:

1. Genetic variants used should be associated with – and explain between 0.5 percent to 1.0 percent of – exposure variance to give the study adequate power.

2. Genetic variants shouldn’t be associated with any factors that confound the exposure-outcome relationship.

3. Genetic variants should only influence outcome through exposure and shouldn’t have pleiotropic effects.

Mendelian Randomization & Rheumatology

To date, Mendelian randomization has been applied mainly to the cause-effect relationship between urate levels and cardiometabolic traits, including coronary heart disease, high blood pressure, diabetes, obesity, body mass index, and kidney function. These studies, which also test for reverse causality, have found genetic variants associated with both hyperuricemia and gout have causal relationships with urate levels. Other studies suggest a causal role for vitamin D levels in determining responses to rheumatoid arthritis therapies and disease outcomes, as well as a causal role for high body mass index and osteoarthritis risk.

An existing literature review also revealed causal relationship results based on Mendelian randomization.

IL-1 signalling in Rheumatoid Arthritis: Investigators used Mendelian randomization to unearth cardiovascular risks of long-term inhibition of IL-1 signalling. The study used two genetic variants affecting the gene that encodes IL-1 receptor antagonist (IL-1RA) and included 453,411 participants. Results indicated alleles associated with elevated IL-1RA expression were also linked to protection from rheumatoid arthritis and a cardiovascular disease increase.

Phosphate and Bone Mineral Density: According to Mendelian randomization, high phosphate intake affects calcium metabolism. The study, involving fewer than 200 patients, tested the genetic variant FGF23 associated with phosphate levels to identify any causal relationship with bone mineral density in children. The result was null.

Serum urate levels: Although genetic variation in five genes involved with uric acid excretion account for 3 percent to 4 percent of variance in serum urate levels, Mendelian randomization studies don’t point to a causal role for serum urate levels in hyperuricemia phenotypes, including poor kidney function, ischemic heart disease, diabetes, high blood pressure, high cholesterol, high bone mineral density, and high body mass index.

Rheumatoid Arthritis and Cardiovascular Disease: Rheumatoid arthritis is associated with a higher cardiovascular disease risk, and LDL cholesterol-associated genetic variants could help determine which drives the other. Mendelian randomization could also inform the paradoxical relationship between low body mass index and high mortality with rheumatoid arthritis.

Gout and Other Metabolic Diseases: Any causal relationships between gout and comorbidities are unknown. According to researchers, Mendelian randomization studies could be designed to focus on the disease’s inflammatory aspects to reveal existing links.

Urate Levels and Neurological Disease: Research shows urate levels protect against neurodegenerative condition development, including Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis. Using Mendelian randomization to determine whether this relationship is causal could play into how aggressively providers approach reducing urate in gout.

Urate Levels and Cancer: The potential urate level and cancer risk link has been well reported and is assumed to be the result of urate’s oxidative intracellular action. However, some studies find those resuls inconclusive. It’s possible the serum urate level effect on cancer risk could be location and malignancy-type dependent.

Overall, researchers said, the urate, gout, and cancer association is complex. Existing studies found higher cancer rates in patients with gout versus those without the condition. Others found no association.

Additionally, genetic variants are mostly pulled from genome-wide association studies conducted on middle-aged and older adults. Consequently, any detected effects could arise from years of cumulative environmental exposures. As a result, investigators recommended returning to Mendelian randomization’s origins where any exposure effect on outcomes would be tested with linear or logistic regression only.

“This proposal also contains the suggestion,” researchers wrote, “that Mendelian randomization is particularly valuable in establishing null results in a large, well-powered sample sets with an established association between genetic variant and exposure but no association between genetic variant and outcomes, supporting the conclusion that little or no effect of exposure on outcome exists.”

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I’m a seasoned reporter, writer, freelancer and public relations specialist with a master’s degree in international print journalism from The American University in Washington, D.C.

I launched my journalism career as a stringer for UPI on Sept. 11, 2001, on Capitol Hill. That day led to a two-year stint as a daily political reporter in Montgomery County, Md. As a staff writer for the Association of American Medical Colleges, a public relations specialist for the Duke University Medical Center and the public relations director for the UNC-Chapel Hill School of Nursing, I’ve earned in-depth experience in covering health care, including academic medicine, health care reform, women’s health, pediatrics, radiology, and Medicare.